Front-line High-Dose Chemotherapy with Rituximab Showed Excellent Long-Term Survival in Adults with Aggressive Large B-Cell Lymphoma: Final Results of a Phase II GOELAMS Study

Abstract Introduction : Central nervous system (CNS) relapse is a devastating complication affecting ~5% of patients with diffuse large B-cell lymphoma (DLBCL). The optimal management is unknown and survival rates are ~20% in contemporary series. Thiotepa/busulfan-based high-dose chemotherapy (HDT) and autotransplant (ASCT) has demonstrated efficacy in primary CNS lymphoma, but there have been fewer studies of this conditioning regimen in secondary CNS lymphoma (SCNSL). Methods : This multicenter retrospective study included all consecutive patients ≥18 years old with aggressive B-cell lymphoma and secondary CNS involvement treated with thiotepa/busulfan-based HDT/ASCT at the University of Calgary and University of Alberta since 2005. Kaplan-Meier curves were used to estimate progression-free survival (PFS), overall survival (OS), and disease-specific survival (DSS) from the time of ASCT. Data collection is underway for all consecutively diagnosed SCNSL patients at our institutions to evaluate frequency and predictors of HDT/ASCT use. Results : This study included 57 patients with DLBCL (n=45), double-hit lymphoma (n=6), high-grade B-cell lymphoma NOS (n=2), intravascular large B-cell lymphoma (n=2), or T-cell/histiocyte-rich large B-cell lymphoma (n=2). Two (4%) had previously treated indolent B-cell lymphoma and 1 (2%) had multiply relapsed DLBCL. Median International Prognostic Index was 4 (range 0-5) at DLBCL diagnosis and median time to CNS relapse was 4 months (range 0-139). Median age was 58 years (range 20-73) and median ECOG was 3 (range 0-4) at diagnosis of SCNSL. CNS involvement was present at initial diagnosis in 20 (35%) patients or developed during frontline treatment in 10 (18%) or after completion of treatment in 27 (47%). For those without SCNSL at diagnosis, isolated CNS relapse occurred in 31 (84%) patients while 6 (16%) had concurrent CNS and systemic relapse. Most patients (n=54, 94%) received high-dose methotrexate (HD-MTX)-based multiagent induction chemotherapy (median HD-MTX doses 4, range 1-5) followed by peripheral blood stem cell mobilization with rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP) in 41 (72%). HDT conditioning regimens were thiotepa, busulfan, melphalan, rituximab (TBMR, n=52, 91%) or thiotepa, busulfan, cyclophosphamide (TBC, n=5, 9%). Median time from SCNSL diagnosis to ASCT was 116 days (range 7-201). Median time to neutrophil engraftment was 10 days (range 7-15) and to platelet engraftment 16 days (range 9-93). Overall response rates (ORR) for systemic/CNS disease were 93%/89% pre-ASCT and 95%/100% post-ASCT. Combined ORR pre-ASCT was 88%, with complete response in 21% and partial response in 67%. Two (4%) patients who developed CNS relapse immediately prior to ASCT achieved long-term remission after TBMR conditioning without any other systemic chemotherapy. With a median follow-up time of 4.0 years (range 0.1-15.9), PFS was 75% (95% CI 61-85%), OS was 76% (95% CI 62-86%), and DSS was 79% (95% CI 64-88%) at 4 years after ASCT. Lymphoma recurred in 9 (16%) patients at median 88 days (range 54-346) after ASCT with CNS relapse (n=4), systemic relapse (n=3), or both (n=2). There were 2 (4%) deaths due to peri-transplant toxicity and 1 (2%) death at 1.5 years due to therapy-related acute myeloid leukemia; no other unexpected toxicities of HDT/ASCT were observed. Among the 45 (79%) patients achieving long-term disease-specific survival, none were treated with CNS radiation therapy and only 1 (2%) had persistent neurocognitive impairment. There were no significant differences in DSS with respect to timing of CNS relapse, concurrent presence of systemic disease, or TBMR versus TBC conditioning (78% vs 80%, p=0.87). Conclusion : In one of the largest studies of this conditioning regimen in SCNSL to date, we found that high-dose thiotepa/busulfan-based conditioning with ASCT is associated with favorable outcomes for patients with aggressive B-cell lymphoma and secondary CNS involvement, with 4-year OS ~75% in this study. Although SCNSL has been historically associated with a poor prognosis, an increasing proportion of patients may achieve long-term survival after intensive therapy with HD-MTX-based induction and thiotepa/busulfan-based HDT and ASCT. Figure 1 Figure 1. Disclosures Chua: Eisai: Honoraria; Pfizer: Honoraria; Merck: Honoraria; Gilead: Honoraria. Stewart: Novartis: Honoraria; AstraZeneca: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria; Sandoz: Honoraria; Teva: Honoraria.

Download Full-text

Non-Relapse Mortality Exceeds Relapse Mortality Six Years After Autologous Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma.

Blood ◽

10.1182/blood.v114.22.3325.3325 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3325-3325

Author(s):

Brian T. Hill ◽

Lisa Rybicki ◽

Brian J. Bolwell ◽

Stephen Smith ◽

Robert Dean ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

B Cell ◽

Partial Remission ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Term Survival ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Abstract 3325 Poster Board III-213 For patients with diffuse large B-cell lymphoma (DLBCL) who failed to achieve complete remission (CR) or who relapsed after obtaining CR with initial treatment, salvage therapy has historically resulted in poor long-term survival. The PARMA trial identified high dose chemotherapy followed by autologous stem cell transplantation (ASCT) as a superior treatment modality compared to standard chemotherapy. As originally reported in 1995, the 5-year event-free-survival (EFS) was 46% in patients undergoing ASCT, compared to 12% in patients receiving chemotherapy alone. Subsequent to the widespread adoption of ASCT, it has been noted that patients who have undergone autologous transplantation for relapsed or refractory DLBCL may be at increased risk of mortality well beyond 5 year point which has generally been an accepted surrogate for long-term survival. To assess long-term outcomes of these patients, we retrospectively analyzed data from 309 consecutive patients who received ASCT for DLBCL at the Cleveland Clinic from January 1994 through December 2006. Inclusion criteria were age ≥ 18 years, diagnosis of DLCBL, and history of a single autologous stem cell transplant. The median age of these patients was 51 years (range 19-72) and 61.2% were male. The median time from diagnosis of DLBCL to transplant was 14.7 months (range 2.1-372.3). 99.0% of patients received peripheral blood stem cells and 98.4% received a preparative regimen with busulfan/cyclophosphamide/VP16. As shown in the accompanying figure, non-relapse mortality (NRM) becomes the major cause of death approximately 6 years after ASCT. The most common causes of NRM during the study period were pulmonary toxicity (31%), infection (17%), cardiac toxicity (15%) and secondary malignancy (15%). In multivariate analysis, the strongest predictor of relapse mortality was disease status at transplant: patients who were in second complete or partial remission had a higher risk of relapse mortality than those in first complete or partial remission (hazard ratio [HR] 3.70, P<0.001), as did those who were relapsed or refractory (HR 4.85, P<0.001) Significant risk factors for NRM were older age (HR 1.43, P=0.017 per 10 year increase), prior chemotherapy (HR 1.31, P=0.030 per 1 regimen increase), and poor performance status at the time of transplant (HR 4.66, P=0.010 for KPS 50-80 relative to KPS 100). In conclusion, we describe the longest reported follow-up of a large cohort of DLBCL patients uniformly-treated with ASCT. We have found that although relapse is initially the more likely cause of death, after six years, NRM exceeds relapse mortality. As more patients with DLBCL survive ASCT, these findings emphasize the need for active surveillance for causes of morbidity and mortality other than relapsed lymphoma. Disclosures No relevant conflicts of interest to declare.

Download Full-text